Gene expression profiling in chronic copper overload reveals upregulation of Prnp and App
Gene expression profiling in chronic copper overload reveals upregulation of Prnp and App
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DOI：
10.1152/physiolgenomics.00196.2003
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发表时间：
2004-12-15
影响因子：
4.6
通讯作者：
Vulpe, CD
中科院分区：
文献类型：
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作者：
Armendariz, AD;Gonzalez, M;Vulpe, CD
铜的中毒水平尚不清楚。几项研究表明，铜会导致氧化应激；然而，大多数人的铜暴露水平都很高。我们目前对长期接触铜的细胞中的保护系统只有有限的了解。此外，体内平衡调节的极限尚不清楚，因此很难确定铜过量的温和影响。此外，需要一种强大的检测方法来促进铜过量的诊断，并区分轻度、中度和重度铜超载。为了解决这些问题，我们利用cDNA微阵列研究了慢性铜超载对细胞培养模型系统中稳态基因表达的影响。在这项研究中，我们使用了来自铜过载遗传模型的细胞：来自两种小鼠突变体C57BL/6-Atp7a（Mobr）和C57BL/6-Atp7a（Modap）的成纤维细胞。这些细胞系在正常培养基中由于铜输出缺陷而积累到异常高的水平。我们用离群值鉴定方法鉴定了12个共同的差异表达基因。令人惊讶的是，我们的结果显示在含铜细胞中没有氧化应激的证据。此外，候选组分可能负责铜特异性稳态响应被确定。朊病毒蛋白和淀粉样蛋白前体蛋白（两种已知的铜结合蛋白）的编码基因在两种细胞系中都被上调。
The level at which copper becomes toxic is not clear. Several studies have indicated that copper causes oxidative stress; however, most have tested very high levels of copper exposure. We currently have only a limited understanding of the protective systems that operate in cells chronically exposed to copper. Additionally, the limits of homeostatic regulation are not known, making it difficult to define the milder effects of copper excess. Furthermore, a robust assay to facilitate the diagnosis of copper excess and to distinguish mild, moderate, and severe copper overload is needed. To address these issues, we have investigated the effects on steady-state gene expression of chronic copper overload in a cell culture model system using cDNA microarrays. For this study we utilized cells from genetic models of copper overload: fibroblast cells from two mouse mutants, C57BL/6-Atp7a(Mobr) and C57BL/6-Atp7a(Modap). These cell lines accumulate copper to abnormally high levels in normal culture media due to a defect in copper export from the cell. We identified 12 differentially expressed genes in common using our outlier identification methods. Surprisingly, our results show no evidence of oxidative stress in the copper-loaded cells. In addition, candidate components perhaps responsible for a copper-specific homeostatic response are identified. The genes that encode for the prion protein and the amyloid-beta precursor protein, two known copper-binding proteins, are upregulated in both cell lines.